Anti-inflammatory pharmaceutical formulations

ABSTRACT

An oral pharmaceutical dosage form including a mixture of a delay release formulation of a non-steroidal anti-inflammatory drug (NSAID) and a mixture containing a prostaqlandin and one or more excipients.

This application is a Continuation of prior Application Ser. No.10/002,411, filed Nov. 14, 2001, now U.S. Pat. No. 6,537,582; Ser. No.09/479,430, filed Jan. 7, 2000, now U.S. Pat. No. 6,387,410;Continuation-in-Part of application Ser. No. 09/414,673, filed Oct. 7,1999, now abandoned; Continuation-in-Part of application Ser. No.09/394,179, filed Sep. 10, 1999, now abandoned; and ProvisionalApplication No.: 60/099,814, filed on Sep. 10, 1998, from which priorityunder 35 U.S.C. §120 is claimed.

This invention relates to pharmaceutical formulations ofanti-inflammatory drugs, particularly non-steroidal anti-inflammatorydrugs (NSAIDs).

These NSAIDs are used for the treatment of inflammatory conditions suchas osteoarthritis or rheumatoid arthritis. A side effect of the oraladministration of NSAIDs particularly with long term usage, is aliability to ulcerogenic effects. NSAID induced ulcers in the stomachare potentially dangerous because few or no symptoms may be detecteduntil significant damage has been caused. Certain prostaglandins, forexample misoprostol have been shown to reduce and even prevent suchulcers.

Various patent applications relate to use of misoprostol with immediaterelease drugs, for example GB-A2135881 (Farmitalia Carlo Erba),W091/16896 (G D Searle), or where a gastric resistant coating is putover the NSAID in an attempt to reduce further gastric erosion due torelease in the stomach of the NSAID, for example W091/16895, W091/16886(G D Searle).

There is an increasing use of sustained release preparations of NSAIDdrugs to reduce the number of doses required by the patient each day.Although the theory of such preparations is that the majority of thedrug is released in the intestine rather than the stomach, in practicethere is a significant occurrence of gastric problems. This may be dueto release of small amounts of drug within the stomach.

The incorporation of misoprostol into such products to reduce thepotential for such problems has not previously been disclosed.

According to the present invention an oral pharmaceutical dosage formincludes a mixture of a delay release formulation of a NSAID and amixture containing one or more excipients and a prostaglandin.

The delay release NSAID formulation preferably comprises coated beads orpellets.

An alternative formulation comprises coated granules.

The prostaglandin mixture may be provided in the form of a powder whichis mixed with the NSAID formulation within the dosage form.

The dosage form may comprise a tablet, capsule, granule or othercommonly used configuration. However preferred dosage forms comprise acapsule containing multi-particulate beads or granules of the NSAIDformulation together with the powdered prostaglandin mixture. The NSAIDbeads or granules preferably have coatings adapted to provide programmedrelease according to the position in the gastrointestinal tract. Use ofsuch coated beads or granules provides a more repeatable release alongthe gastrointestinal tract and may reduce gastric erosion because thesmall pellets or beads are easily moved and do not adhere readily to thefolds of the gastric wall.

Beads or granules for use in accordance with this invention may have asingle slowly erodible coat or may comprise mixtures of beads orgranules with differing levels or types of coating adapted to provide acontinuous or distributed release profile through the gastrointestinaltract. The delay afforded may range from a minimal delay to severalhours, dependent on the pH of the gastrointestinal tract in theimmediate vicinity.

The NSAID is preferably but not exclusively one of reasonably low weightper standard dose, that is 200 mg or below. Examples of suitable NSAIDsinclude tiaprofenic acid, piroxicam, flubiprofen, tenoxicam, meloxicamor similar molecules. Salts or other derivatives of these drugs may beemployed in a conventional manner. Most preferably the drug isdiclofenac sodium, ketoprofen or indomethacin. Mixtures may be used.

It is possible to produce the particles or beads by conventional means.Techniques that can be used can include coating the drug on a non-parielcore preferably composed of inert sugar or similar substance and thenovercoating with the required coating before encapsulation. Thefollowing steps may be employed.

i. Preparation of inert core by conventional pan coating method

ii. Active coating by using rotary type fluidized bed.

iii. Protective coating by using rotary type fluidized bed.

iv. Enteric coating by using rotary type fluidized bed.

The procedure disclosed in EP-A-519144 may be used.

Drug delivery using capsules avoids a further compression step as may benecessary during tablet manufacture.

An alternative method is to form beads or particles by co-acervation oralternatively by precipitation from solution as described by Zaniboni,Fell and Collett, (Int.J.Pharm, 1995, 125, 151-5).

In a preferred technique the beads or particles may be formed byspheronisation, rotogranulation or a similar technique. If tablets areto be made, preferably the beads or particles should be soft enough todeform slightly under compression to avoid cracking but not too soft soas to deform significantly as deformation may also cause cracking orrupture of the coat. A mixture of drug with a suitable amount of anexcipient or excipients can be found by simple experiments. Suitableexcipients include polyvinyl pyrrolidone, sugars and cellulosederivatives particularly microcrystalline cellulose.

Granules, for example composed of diclofenac sodium and a methylmethacrylate (eg Eudragit L 30 D-55) may be prepared by blending theingredients in a planetary mixer with slow addition of water to producegranules. In a preferred process very fine granules are produced toavoid a need for milling before compaction into tablets or incorporationinto capsules. Use of granules with the dimension of 200-1000 μm,preferably 300 to 500 μm is particularly suitable. Tablets may beproduced by coating these granules with a barrier coating material forexample a cellulosic material such as hydroxypropylmethyl cellulose orhydroxypropyl cellulose. Tablets may be produced by coating thesegranules.

An alternative method of forming coated granules is by spraying asolution of Eudragit onto a bed of diclofenac sodium or other drug andany necessary excipients for example using a fluid bed coatingapparatus. The process is preferably controlled to produce fine granuleswhich do not require milling before incorporation into tablets orcapsules.

The coating for the beads may include cellulose derivatives eghydroxypropyl methyl cellulose, methacrylic acid and derivatives egmethyl methacrylates for example, Eudragrit® (Rhom Pharm), especiallyEudragrit L or S. Other standard enteric coating materials may be usedfor example phthalates, eg cellulose acetate phthalate or preferablyhydroxypropylacetate phthalate or polyvinylacetate phthalate. Mixturesof these and other materials may be used to produce delay release coatedbeads. Normally the coating will include plasticisers eg polyethyleneglycol, triacetin or phthalate esters.

The prostaglandin component preferably contains misoprostol optionallytogether with one or more inert excipients. The prostaglandin isnormally provided as a 1:10 or 1:100 dilution on an inert cellulose orother binder or filler. Especially useful material for this invention ishydroxypropyl methyl cellulose. The dosage of prostaglandin may bechosen to be suitable to prevent or reduce stomach ulceration caused bythe NSAID. A suitable dose of misoprostol is between 10-50 μg preferably50-200 μg per dosage form but this may be increased or decreaseddepending on the NSAID used.

Preferred dosage forms comprise capsules, preferably hard gelatincapsules.

Tablets where the prostaglandin is mixed with one or more binding agentsmay be bi-layer tablets wherein the NSAID is formed into a first layerand the prostaglandin is then compressed onto it. A tri-layer tabletwith an inert intermediate barrier layer between the NSAID andprostaglandin layers may be employed.

In preferred embodiments of the invention, the potential for gastricerosion is reduced by ensuring that the prostaglandin is released beforethe NSAID. Any beads for immediate or rapid release are coated with aninert coating which defer solubility in gastric fluid, for example for aperiod of 30 minutes. Such materials include cellulose derivatives forexample hydroxypropyl methyl cellulose, methyl or ethyl celluloses orother sealants eg Zein. Thin coatings of methacrylate derivatives egpolyhydroxymethacrylate or other materials such as hardened gelatine,waxes, starches or polyvinyl pyrrolidone may be used. Other portions ofthe beads may be coated with methacrylate derivatives, phthalate, forexample hydroxypropyl methyl cellulose phthalate or similar materials togive an appropriate release profile as is well known in the art.

The invention is further described by means of example, but not in anylimitative sense.

EXAMPLE 1

Hard gelatin capsules fill was prepared containing a mixture of thefollowing:

delay release ketoprofen beads 250 mg misoprostol (diluted 1:100 onhydroxypropylmethylcellulose)  20 mg lactose (anhydrous) 160 mghydrogenated vegetable oil  4 mg

The beads were prepared by spray coating a suspension or solution ofketoprofen onto a non-pareil sugarcore, together with a binder egpolyvinylpyrollidone or hydroxypropylmethyl cellulose. The beads weresubsequently coated with a delay release coating eg methylmethacrylate(eg Eudragit (Trade Mark)). Mixtures of beads with various levels ofcoating were used to give the required therapeutic release pattern.

In a fluidized bed apparatus, uniform spherical inert sugar sphere coreswere coated with a first layer consisting of the compounds, an inertwater soluble polymer such as hydroxy-propylmethylcellulose orhydroxypropylcellulose, and talc. The second layer consisted of an inertwater soluble polymer such as hydroxypropylmethylcellulose orhydroxypropylcellulose, talc and a pigment such as titanium dioxide. Thethird and enteric coating layer consisted of an enteric coating polymersuch as co-polymerized methacrylic acid/methacrylic acid methyl esters,a plasticiser such as triethy acetate or similar plasticisers, and talc.

The layers were applied by conventional fluidized bed coating techniquesusing aqueous solutions or dispersions.

Pseudo zero release was obtained by use of a mixture of beads releasedat various pHs or at various times dependent on the type of coating.

The beads in Example 1 contained 40% ketoprofen giving a dose percapsule of 100 mg plus 100 μg misoprostol.

The mix was then filled into suitable hard gelatine capsules.

EXAMPLE 2

The following formulation was employed:

delay release diclofenac beads 214 mg microcrystalline cellulose (dried)eg Avicel R PH112 150 mg misoprostol (1 in 100 dilution on HPMC) 20 mgstearic acid 4 mg talc g mg

EXAMPLE 3

The following formulation was mixed with water in a planetary mixer tomake enteric coated granules:

diclofenac sodium 96.28 Eudragit L 30 D-55 3.8%

The granules were dried and compacted into layered tablets having thefollowing composition:

diclofenac-containing granules 26.0% microcrystalline cellulose 73.5%magnesium stearate  0.5%

The tablets were compared to a proprietary diclofenac containing tabletavailable under the trade mark Arthrotec. Bioequivalence studies showedthe properties to be essentially similar.

Beads containing 35% diclofenac sodium ie 75 mg drug per dose wereprepared.

The beads were formed as previously described, or by mixing with abulking agent eg microcrystalline cellulose, moistening with water,extruding and spheronising to give spherical or ovoid particles about0.5 mm to 1.5 mm in diameter. These were dried and coated as previouslydescribed using a standard coating agent. The beads were mixed asrequired to give the required release profile.

The beads are usually provided with a coating to prevent immediaterelease in the stomach, particularly release before the misoprostol hasdissolved.

EXAMPLE 4

A two layer tablet was made as follows:

The following ingredients were mixed together:

Diclofenac sodium 75.95% Eudragit 130-d55 (30% solid dispersion) 12.66%Lactose (20 mesh)  11.4% Water

The mixture was blended, dried and milled to give diclofenac-containinggranules. The granules (25%) were mixed with microcrystalline cellulose(Avicel pH 200 and pH 112) to give a total of 69%. Dry Eudragit 1100powder (5%) and hydrogenated castor oil (1%) were added. The mixture waspressed into half tablets with a tablet weight of 400 mg.

A misoprostol layer was formed as follows:

A misoprostol dispersion (1:100) 6.7% was combined with microcrystallinecellulose (Avicel pH 112) 88.33%, croscarmelose sodium (4%) andhydrogenated castor oil to give a tablet weight of 300 mg. The combinedbi-layered tablet had a total weight of 700 mg.

Dissolution properties were determined by exposure to acid medium fortwo hours followed by measurement of dissolution in alkaline buffer. Thefollowing results were obtained.

SOLUBILITY Time in alkaline buffer Example 4 tablets Arthrotec tablets30 sec 1.6-5.0   0-0.5 5 min 11-13 1.3-3.1 30 min 51-60 61-71 60 min86-90 74-96

What is claimed is:
 1. An oral pharmaceutical dosage form, comprising ahard gelatin capsule filled with a mixture of a delay releaseformulation of a non-steroidal anti-inflammatory drug (NSAID) and amixture containing a prostaglandin and one or more excipients, whereinthe prostaglandin mixture is a powder and the dosage form containsmulti-particulate coated particles selected from the group consisting ofbeads and granules of the NSAID formulation together with the powderedprostaglandin mixture.
 2. A dosage from as claimed in claim 1, whereinthe NSAID formulation comprises coated granules.
 3. A dosage form asclaimed in claim 2, wherein the granules have a dimension of 200-1000μm.
 4. A dosage form as claimed in claim 3, wherein the granules have adimension of 300-500 μm.
 5. A dosage form as claimed in claim 1, whereinthe prostaglandin is misoprostol.
 6. A dosage form as claimed in claim1, comprising a mixture of beads or granules with different levels ortypes of coating.
 7. A dosage form as claimed in claim 1, wherein theNSAID is selected from the group consisting of tiaprofenic acid,piroxicam, flubiprofen, tenoxicam, meloxicam and salts and derivativesthereof.
 8. A dosage from as claimed in claim 7, wherein the NSAID isselected from the group consisting of diclofenac sodium, ketoprofen andindomethacin and mixtures thereof.
 9. A dosage form as claimed in claim5, wherein the dosage of misoprostol is 50 to 200 μg per dosage form.10. An oral pharmaceutical dosage form, comprising a bi-layer ortri-layer tablet with a mixture of a delay release formulation of anon-steroidal anti-flammatory drug (NSAID) and a mixture containing aprostaglandin and one or more excipients, wherein the prostaglandinmixture is a powder and the dosage form contains multi-particulatecoated particles selected from the group consisting of beads andgranules of the NSAID formulation together with the powderedprostaglandin mixture.
 11. A dosage form as claimed in claim 10, whereinthe beads or granules of the NSAID are coated with a coating selectedfrom the group consisting of: hydroxypropyl methyl cellulose,methacrylic acid and derivatives, methyl methacrylates, celluloseacetate phthalate, hydroxypropylacetate phthalate, polyvinylacetatephthalate and mixtures thereof are compressed into a first layer and asecond layer comprising the prostaglandin and excipients is compressedonto the first layer.
 12. A dosage form as claimed in claim 10,comprising a mixture of beads or granules with different levels or typesof coating.
 13. A dosage form as claimed in claim 10, wherein the NSAIDis selected from the group consisting of tiaprofenic acid, piroxicam,flubiprofen, tenoxicam, meloxicam and salts and derivatives thereof. 14.A dosage form as claimed in claim 10, wherein the NSAID is selected fromthe group consisting of diclofenac sodium, ketoprofen and indomethacinand mixtures thereof.
 15. A dosage form as claimed in claim 10, whereinthe prostaglandin is misoprostol.
 16. A dosage form as claimed in claim15, wherein the dosage of misoprostol is 50 to 200 μg per dosage form.